The primary goal of this CCNE project is to develop a new class of self-assembled and biodegradable nanoparticles for delivery and targeting of cytotoxic chemotherapeutic drugs to solid tumors. The use of nanoparticles for drug delivery and targeting is one of the most advanced, exciting, and clinically important applications of nanotechnology. Recent advances have led to the FDA approval of albumin-conjugated . paclitaxel or Taxol[unreadable] (Abraxane), a "binary" nanoparticle for treatment of taxane-refractory breast cancer. Research by this CCNE team has developed a more sophisticated "ternary" nanoparticle structure by linking both a hydrophobic cancer drug (Taxol[unreadable]) and a tumor-targeting ligand (folic acid or FA) to a hydrophilic and biodegradable polymer (Heparin). The antitumor activity of this ternary nanoparticle (Heparin-FA-Taxol[unreadable]) is nearly 17 times more higher than the free drug in the xenograft tumor models. These results have raised new possibilities in developing targeted nanoparticle drugs for cancer therapy. In this project, we propose to develop several series of multifunctional nanoparticle therapeutics by using three taxane drugs (paclitaxel, docetaxel, and epothilone B), two targeting ligands (e.g., folic acid and a single-chain antibody fragment against EGFR), and biodegradable carriers (e.g., heparin and polyglutamic acid). Initial studies will focus on the Heparin-FA-Taxol[unreadable] nanoparticle because of our extensive experience with this conjugate and its excellent drug delivery and targeting properties. Other combinations will also be explored, and will be critically evaluated and compared with free drugs in both in-vitro and in-vivo systems. Promising nanoparticles will be further evaluated by the CCNE Assessment Committee for the possibility of moving toward preclinical toxicology, pharmacokinetic, and pharmacodynamic studies. To this end, we propose to test the hypotheses that tumor targeted novel therapeutic nanoparticles will improve (i) delivery and tumor specific distribution of anticancer drugs, (ii) will enhance intracellular concentration of anticancer agents to minimize drug resistance leading to much improved therapeutic indeces for common anticancer drugs. The proposed research has the following specific aims. Aim 1: Development of self-assembled, biodegradable and multifunctional nanoparticles for delivery and targeting of anticancer drugs. Aim 2: Elucidation of biological and molecular effects of taxane-conjugated nanoparticles and possibilities in overcoming taxane resistance. Aim 3: Mechanistic investigations of the interaction between novel therapeutic nanoparticles and cancer cells in vitro. Aim 4: Toxicology studies using mouse, rat, and rabbit, and efficacy of the novel therapeutic nanoparticles and assessment of antitumor activities in xenograft models. This study will be conducted by a strong collaborative and interdisciplinary team of medicinal chemists, biomedical engineers, molecular biologists and clinical experts, and will significantly improve drug delivery to the cancer patients